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Volume 12
Issue 4
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Medicines, Volume 12, Issue 4 (December 2025) – 4 articles

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21 pages, 4067 KB  
Article
HDAC5 Inhibition as a Therapeutic Strategy for Titin Deficiency-Induced Cardiac Remodeling: Insights from Human iPSC Models
by Arif Ul Hasan, Sachiko Sato, Mami Obara, Yukiko Kondo and Eiichi Taira
Medicines 2025, 12(4), 26; https://doi.org/10.3390/medicines12040026 - 27 Oct 2025
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Abstract
Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN [...] Read more.
Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies. Full article
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12 pages, 892 KB  
Article
Checklist-Based Identification of Adverse Drug Reactions in Emergency Department Patients
by Benjamin J. Hellinger, Thilo Bertsche, Yvonne Remane and André Gries
Medicines 2025, 12(4), 25; https://doi.org/10.3390/medicines12040025 - 17 Oct 2025
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Abstract
Background: Patients presenting at the emergency department (ED) have a wide variety of complaints. In some of those patients a possible reason for their complaints might be an adverse drug reaction (ADR). An appropriate identification of ADR in this setting is required to [...] Read more.
Background: Patients presenting at the emergency department (ED) have a wide variety of complaints. In some of those patients a possible reason for their complaints might be an adverse drug reaction (ADR). An appropriate identification of ADR in this setting is required to optimize drug therapy and to prevent serious harm deriving from an overlooked ADR. Methods: This retrospective study assessed medical records of patients for ADR as a reason for the ED presentation in two assessments. In the first assessment, medical records were evaluated for potential ADR leading to ED presentation with a predefined checklist by an examiner not involved in initial patient treatment. In the second assessment the same medical records were assessed for ADR identified by the physician in the initial patient presentation. Discrepancies in identified ADR were compared. For descriptive data analysis and statistical evaluation, the McNemar test was performed. Results: From 35,333 patients admitted to the ED, full data were available from 34,747 patients for evaluation. In those patients, 2071 (6.0%) ADR were identified as being the reason for ED presentation by using the checklist. In 828 (2.4%) patients, emergency department physicians had documented an ADR in the medical records. By using the checklist, ADR identification could be improved significantly as compared to routine care, at 6.0% vs. 2.4%, respectively (p < 0.001). The most common chief complaint in patients with an ADR was worsened general condition. Most common drug class causing ADR were antithrombotics. Conclusions: ADR seem to be overlooked in routine care since a significantly higher number of ADR were found by using a checklist-based method as compared to ADR documented as part of routine examination. Therefore, implementing the checklist in the routine process might improve ADR identification. Full article
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13 pages, 1524 KB  
Article
Impact of Sampling Strategy and Population Model on Bayesian Estimates of Vancomycin AUC in Patients with BMI > 40 kg/m2: A Single-Center Retrospective Study
by Sarah A. Ekkelboom, Soraya M. Hobart, Laurie J. Barten and Staci L. Hemmer
Medicines 2025, 12(4), 24; https://doi.org/10.3390/medicines12040024 - 30 Sep 2025
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Abstract
Background/Objectives: Growing evidence supports the use of a single trough concentration, rather than both a peak and trough, to estimate the 24 h area under the curve (AUC24) of vancomycin using Bayesian software (InsightRx® Ver.1.71). However, patients with body [...] Read more.
Background/Objectives: Growing evidence supports the use of a single trough concentration, rather than both a peak and trough, to estimate the 24 h area under the curve (AUC24) of vancomycin using Bayesian software (InsightRx® Ver.1.71). However, patients with body mass index (BMI) ≥ 40 kg/m2 are underrepresented in validation studies. Studies in patients with obesity have produced mixed results, potentially because of different population models used. Methods: This single-center, retrospective study evaluated adult inpatients with BMI ≥ 40 kg/m2. Steady-state AUC24 estimates generated by Bayesian software using both two-concentration and one-concentration inputs were compared. Agreement was defined as a percent difference within ±20%. Subgroup analyses were conducted for patients with defined peak and trough concentrations and for comparisons between two Bayesian population models (Carreno vs. Hughes). Linear regression assessed covariates associated with percent difference. Results: Among 82 encounters, 97.5% of one-concentration estimates based on the smaller concentration were within ±20% of the two-concentration AUC24,SS (mean difference: 2.9%, 95% CI: 0.14 to 3.8%). Similar agreement was observed using the larger concentration (97.5%, mean difference: −3.1%, 95% CI: −4.7 to −0.1.5%). Subgroup analysis for encounters with true peak/trough levels (n = 22) also showed 100% agreement within ±20%. The percent difference did not correlate with BMI or other covariates. Comparison of Hughes vs. Carreno models showed larger variability (only 59.1% within ±20%). Conclusions: In patients with BMI ≥ 40 kg/m2, Bayesian AUC24,SS estimation using a single vancomycin concentration is feasible. Greater caution is warranted in the setting of acute kidney injury, poor model fit, or targeting AUC at the extremes of the therapeutic range. The population model used to generate the Bayesian AUC estimate has a much greater influence than the number of concentrations analyzed. Furthermore, measuring two concentrations does not ensure concordance between models. Full article
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17 pages, 1617 KB  
Systematic Review
Levosimendan in Decompensated Heart Failure with Reduced Ejection Fraction in Older Adults: A Systematic Review of Safety and Efficacy
by Esteban Zavaleta-Monestel, Jeaustin Mora-Jiménez, Kevin Cruz-Mora, Ernesto Martinez-Vargas, José Pablo Díaz-Madriz, Sebastián Arguedas-Chacón, Abigail Fallas-Mora, Carlos Wu-Chin and Jose Miguel Chaverrí-Fernandez
Medicines 2025, 12(4), 23; https://doi.org/10.3390/medicines12040023 - 30 Sep 2025
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Abstract
Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and functional decline in older adults, accounting for over 80% of all heart failure cases. Given the narrow therapeutic window of currently available inotropes and the vulnerability of this [...] Read more.
Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and functional decline in older adults, accounting for over 80% of all heart failure cases. Given the narrow therapeutic window of currently available inotropes and the vulnerability of this population, levosimendan has been proposed as a potential alternative. This systematic review aimed to evaluate the clinical efficacy and safety of levosimendan in older adults with decompensated HFrEF. Methods: A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted between January and May 2025, following PRISMA 2020 guidelines. The review was registered in PROSPERO (CRD420251032329). Of 379 articles initially identified, 8 studies (randomized, observational, and single-arm designs) enrolling patients aged ≥65 years with decompensated HFrEF met the inclusion criteria. Study quality was assessed using the Cochrane RoB-2 tool and JBI Critical Appraisal Checklists. No meta-analysis was performed due to heterogeneity in study designs, populations, and interventions. Results: A total of 2838 patients were analyzed. Levosimendan was associated with short-term improvements in hemodynamic parameters, including an increase in cardiac index (from 1.65 to 2.37 L/min/m2) and a reduction in pulmonary capillary wedge pressure (from 31 to 16 mmHg) within 24–72 h (p < 0.002). However, no statistically significant differences were observed in 30-, 90-, or 180-day mortality (p > 0.05), and findings on rehospitalization were inconsistent. Reported adverse events included hypotension (36–57%) and atrial arrhythmias (9–50%), with low treatment discontinuation rates (5–8%). Conclusions: Levosimendan may improve short-term hemodynamic parameters in older adults with decompensated HFrEF, but the available evidence is limited and heterogeneous. Its effects on mortality and rehospitalization remain inconclusive. Clinical use should be individualized and closely monitored, particularly in frail patients. Full article
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